Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3652-3657. doi: 10.1016/j.bmcl.2018.10.036. Epub 2018 Oct 24.


Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.

Keywords: Anticancer agent; Central nervous system; Optimization; Penfluridol; Repurposing; Toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Penfluridol / analogs & derivatives*
  • Penfluridol / metabolism
  • Penfluridol / pharmacology
  • Penfluridol / therapeutic use
  • Protein Binding
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship
  • Triple Negative Breast Neoplasms / drug therapy


  • Antineoplastic Agents
  • Antipsychotic Agents
  • Receptors, G-Protein-Coupled
  • Penfluridol